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STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
Open accessAbstract
The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN). However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection. Murine embryonic fibroblasts, as well as antigen presenting cells such as macrophages and dendritic cells (exposed to intracellular B-form DNA, the DNA virus herpes simplex virus 1 (HSV-1) or bacteria Listeria monocytogenes), were found to require STING to initiate effective IFN production. Accordingly, Sting-knockout mice were susceptible to lethal infection after exposure to HSV-1. The importance of STING in facilitating DNA-mediated innate immune responses was further evident because cytotoxic T-cell responses induced by plasmid DNA vaccination were reduced in Sting-deficient animals. In the presence of intracellular DNA, STING relocalized with TANK-binding kinase 1 (TBK1) from the endoplasmic reticulum to perinuclear vesicles containing the exocyst component Sec5 (also known as EXOC2). Collectively, our studies indicate that STING is essential for host defence against DNA pathogens such as HSV-1 and facilitates the adjuvant activity of DNA-based vaccines.
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“TBK1 also activates NF‐κB to induce expression of IFN and inflammatory cytokines.65, 66, 67”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [66]
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Innate Immune Recognition of an AT-Rich Stem-Loop DNA Motif in the Plasmodium falciparum Genome
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“The stimulator of interferon genes (STING) has the essential roles in innate immune response against pathogen infections [9].”
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“…that the exocyst plays a direct role in host defense signaling by marshaling TBK1 and STING (stimulator of interferon genes) in response to cellular detection of viral replication intermediates (Bodemann and White, 2008; Chien et al., 2006; Ishikawa and Barber, 2008; Ishikawa et al., 2009).”
Christensen, M. H., Jensen, S. B., Miettinen, J. J., Luecke, S., Prabakaran, T., Reinert, L. S., Mettenleiter, T. C., Chen, Z. J., Knipe, D. M., Sandri-Goldin, R. M., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201593458 · Cited by 233
“DNA sensing stimulates signaling dependent on the adaptor protein stimulator of interferon genes (STING) (Ishikawa et al , 2009).”
NEMO–IKKβ Are Essential for IRF3 and NF-κB Activation in the cGAS–STING Pathway
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“STING in turn induces the phosphorylation and nuclear translocation of IFN (interferon) regulatory factors (IRFs) (Ishikawa et al. 2009).”
BackgroundOvercoming innate immune barriers that impede AAV gene therapy vectors
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“Mice deficient in cGAS and STING are more susceptible to lethal herpes simplex virus 1 (HSV1) infection because of a decrease in type I IFN response (71, 72).”
BackgroundPattern recognition receptors in innate immunity, host defense, and immunopathology
Suresh, R., & Mosser, D. M. (2013) · AJP Advances in Physiology Education · doi:10.1152/advan.00058.2013 · Cited by 250
Extensive evolutionary and functional diversity among mammalian AIM2-like receptors
Brunette, R. L., Young, J. M., Whitley, D. G., Brodsky, I. E., Malik, H. S., & Stetson, D. B. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20121960 · Cited by 230
“…in defining the ISD sensors, it is becoming clear that the STINGdependent ISD pathway is required for the IFN response to numerous DNA viruses (Ishikawa et al., 2009), retroelements and retroviruses (Stetson et al., 2008; Yan et al., 2010), intracellular bacteria (Ishikawa et al., 2009), and…”
BackgroundSTING Signaling Promotes Inflammation in Experimental Acute Pancreatitis
Zhao, Q., Wei, Y., Pandol, S. J., Li, L., & Habtezion, A. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.01.065 · Cited by 225
The PYHIN protein family as mediators of host defenses
Schattgen, S., & Fitzgerald, K. A. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01053.x · Cited by 224
“Additionally, STING is required for the immune stimulatory response to c-di-GMP in vitro and during infection with L. monocytogenes in vivo.”
BackgroundInfluentialAdenovirus Detection by the cGAS/STING/TBK1 DNA Sensing Cascade
Lam, E., Stein, S. C., & Falck-Pedersen, E. (2013) · Journal of Virology · doi:10.1128/jvi.02702-13 · Cited by 236
“STING (7, 8) functions as an adaptor linking DNA recognition signaling to activation of the TBK1 kinase.”
BackgroundTregoning, J. S., Brown, E. S., Cheeseman, H. M., Flight, K. E., Higham, S. L., Lemm, N.-M., Pierce, B. F., Stirling, D. C., Wang, Z., & Pollock, K. M. (2020) · Clinical & Experimental Immunology · doi:10.1111/cei.13517 · Cited by 226
Intracellular Nucleic Acid Detection in Autoimmunity
Crowl, J. T., Gray, E. E., Pestal, K., Volkman, H. E., & Stetson, D. B. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052331 · Cited by 222
Yang, K., Han, W., Jiang, X., Piffkó, A., Bugno, J., Han, C., Li, S., Liang, H. L., Xu, Z., Zheng, W., et al. (2022) · Nature Nanotechnology · doi:10.1038/s41565-022-01225-x · Cited by 224
Prantner, D., Perkins, D. J., Lai, W., Williams, M. S., Sharma, S., Fitzgerald, K. A., & Vogel, S. N. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.382986 · Cited by 225
“Bonemarrowderivedmacrophages from STINGKO (27) and littermate controls were isolated and cultured as previously described (46).”
BackgroundMethodBiodegradable STING agonist nanoparticles for enhanced cancer immunotherapy
Wilson, D. R., Sen, R., Sunshine, J. C., Pardoll, D. M., Green, J. J., & Kim, Y. J. (2017) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2017.10.013 · Cited by 225
Kuchitsu, Y., Mukai, K., Uematsu, R., Takaada, Y., Shinojima, A., Shindo, R., Shoji, T., Hamano, S., Ogawa, E., Sato, R., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01098-9 · Cited by 233
Self-citationInnate immune recognition of DNA: A recent history
Dempsey, A., & Bowie, A. (2015) · Virology · doi:10.1016/j.virol.2015.03.013 · Cited by 229
“STING was shown to be essential for IFN-β induction by DNA and also by HSV-1, and STING knock out mice were subsequently shown to be impaired in their ability to respond to DNA viruses [27].”
BackgroundStump, C. T., & Dougan, S. K. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.11.011 · Cited by 233
Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity
Gallo, P. M., Rapsinski, G. J., Wilson, R. P., Oppong, G. O., Sriram, U., Goulian, M., Buttaro, B. A., Caricchio, R., Gallucci, S., & Tükel, Ç. (2015) · Immunity · doi:10.1016/j.immuni.2015.06.002 · Cited by 228
“, 2000) and cytosolic STING-dependent DNA sensors, resulting in a type I interferon response (Ishikawa et al., 2009).”
Recognition of nucleic acids by pattern‐recognition receptors and its relevance in autoimmunity
Kawasaki, T., Kawai, T., & Akira, S. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01048.x · Cited by 226
“STING is a multipass membrane protein localized in the ER or in the Golgi membrane, and is distributed from the ER to the perinuclear region, where it is exported to unknown organelles by forming puncta structures along with TBK1 after DNA stimulation (103, 104).”
BackgroundMaster sensors of pathogenic RNA – RIG-I like receptors
Schlee, M. (2013) · Immunobiology · doi:10.1016/j.imbio.2013.06.007 · Cited by 216
“monocytogenes (cyclic di-AMP) or generated downstream of cytosolic DNA recognition (GMP-AMP) in mammalian cells (Ishikawa et al. 2009; Sauer et al. 2011; Sun et al. 2012; Woodward et al. 2010; Wu et al. 2012; Zhong et al. 2008).”
BackgroundDecreased expression of STING predicts poor prognosis in patients with gastric cancer
Song, S., Peng, P., Tang, Z., Zhao, J., Wu, W., Li, H., Shao, M., Li, L., Yang, C., Duan, F., et al. (2017) · Scientific Reports · doi:10.1038/srep39858 · Cited by 219
Resolving systematic errors in widely used enhancer activity assays in human cells
Muerdter, F., Boryń, Ł. M., Woodfin, A. R., Neumayr, C., Rath, M., Zabidi, M. A., Pagani, M., Haberle, V., Kazmar, T., Catarino, R. R., et al. (2018) · Nature Methods · doi:10.1038/nmeth.4534 · Cited by 208
The structural basis for the sensing and binding of cyclic di-GMP by STING
Huang, Y.-H., Liu, X., Du, X., Jiang, Z., & Su, X. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2333 · Cited by 224
Sensing disease and danger: A survey of vertebrate PRRs and their origins
Hansen, J. D., Vojtech, L. N., & Laing, K. J. (2011) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2011.01.008 · Cited by 220
“7, 23. ryan, N.B., Dorfleutner, A., Rojanasakul, Y., Stehlik, C., 2009.”
DNA Sensing in the Innate Immune Response
Briard, B., Place, D. E., & Kanneganti, T. (2020) · Physiology · doi:10.1152/physiol.00022.2019 · Cited by 222
STING-Mediated DNA Sensing Promotes Antitumor and Autoimmune Responses to Dying Cells
Klarquist, J. S., Hennies, C. M., Lehn, M. A., Reboulet, R. A., Feau, S., & Janssen, E. M. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401869 · Cited by 218
Cytosolic DNA sensors regulating type I interferon induction
Keating, S. E., Baran, M., & Bowie, A. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.08.004 · Cited by 212
Viruses and the autophagy pathway
Jackson, W. T. (2015) · Virology · doi:10.1016/j.virol.2015.03.042 · Cited by 215
Zhang, Z., Zhou, H., Ouyang, X., Dong, Y., Sarapultsev, A., Luo, S., & Hu, D. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01252-z · Cited by 222
“Since its discovery, multiple animal data supported that STING knock mice are more susceptible to DNA virus infection.(4) The human and murine hepatocyte has been reported to be devoid of STING expression(199) and a functional innate DNA-sensing pathway, partially explaining the tropism of the hepatitis B virus toward…”
BackgroundInfluentialLee‐Kirsch, M. A. (2016) · Annual Review of Medicine · doi:10.1146/annurev-med-050715-104506 · Cited by 216
Identification and functions of pattern-recognition receptors
Kumagai, Y., & Akira, S. (2010) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2010.01.058 · Cited by 218
Ho, S. S. W., Zhang, W. Y. L., Tan, N. Y., Khatoo, M., Suter, M. A., Tripathi, S., Cheung, F. S. G., Lim, W. K., Tan, P. H., Ngeow, J. Y. Y., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.04.010 · Cited by 213
“Stimulator of interferon (IFN) genes (STING) induces the production of type I IFNs and other pro-inflammatory cytokines following the detection of double-stranded DNA (dsDNA) by cytosolic DNA sensors (Ishikawa et al., 2009).”
BackgroundInfluentialER-directed TREX1 limits cGAS activation at micronuclei
Mohr, L., Toufektchan, E., von Morgen, P., Chu, K., Kapoor, A. R., & Maciejowski, J. (2021) · Molecular Cell · doi:10.1016/j.molcel.2020.12.037 · Cited by 211
“Detection of double-stranded DNA (dsDNA) inside ruptured MN stimulates cGAS catalytic activity and the production of 2′3′-cyclic GMP-AMP (cGAMP) (Ablasser et al., 2013; Civril et al., 2013; Diner et al., 2013; Gao et al., 2013; Sun et al., 2013). cGAMP engages with STING, resulting in activation of the kinase TBK1 and…”
BackgroundMa, X. M., Geng, K., Law, B. Y. K., Wang, P., Pu, Y. L., Chen, Q., Xu, H. W., Tan, X. Z., Jiang, Z. Z., & Xu, Y. (2022) · Cell Biology and Toxicology · doi:10.1007/s10565-021-09692-z · Cited by 206
Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade
Zhang, Q., Meng, F., Chen, S., Plouffe, S. W., Wu, S., Liu, S., Li, X., Zhou, R., Wang, J., Zhao, B., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3496 · Cited by 206
STING-associated vasculopathy develops independently of IRF3 in mice
Warner, J. D., Irizarry-Caro, R. A., Bennion, B. G., Ai, T. L., Smith, A. M., Miner, C. A., Sakai, T., Gonugunta, V. K., Wu, J., Platt, D. J., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20171351 · Cited by 210
“Genetic deletion of STI NG in mice results in impaired immunity to a variety of pathogens including bacteria and viruses (Ishikawa et al., 2009; Schoggins et al., 2014; Parker et al., 2015).”
BackgroundRNF26 Temporally Regulates Virus-Triggered Type I Interferon Induction by Two Distinct Mechanisms
Qin, Y., Zhou, M., Hu, M., Hu, Y.-H., Zhang, J., Guo, L., Zhong, B., & Shu, H. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004358 · Cited by 203
Horan, K., Hansen, K., Jakobsen, M. R., Holm, C. K., Søby, S., Unterholzner, L., Thompson, M., West, J. A., Iversen, M. B., Rasmussen, S. B., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202749 · Cited by 212
“Upon DNA sensing, STING relocalizes to as-yet-uncharacterized cytoplasmic foci, which are believed to serve as assembly platforms for signaling (28).”
BackgroundInfluentialRole of the cGAS–STING pathway in cancer development and oncotherapeutic approaches
Khoo, L. T., & Chen, L. (2018) · The EMBO Reports · doi:10.15252/embr.201846935 · Cited by 204
“Binding of cGAMP to a small pocket of the STING dimer [19,20,23,27] promotes translocation of STING from the endoplasmic reticulum (ER) via the Golgi apparatus to perinuclear microsomes [28,29].”
TLR‐mediated activation of NK cells and their role in bacterial/viral immune responses in mammals
Adib‐Conquy, M., Scott‐Algara, D., Cavaillon, J., & Souza-Fonseca-Guimarães, F. (2013) · Immunology and Cell Biology · doi:10.1038/icb.2013.99 · Cited by 201
STING induces LC3B lipidation onto single-membrane vesicles via the V-ATPase and ATG16L1-WD40 domain
Fischer, T. D., Wang, C., Padman, B. S., Lazarou, M., & Youle, R. J. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.202009128 · Cited by 206
Metadata
- Authors
- Ishikawa, H., Ma, Z., & Barber, G. N.
- Affiliations
- University of Miami (US)
- Corresponding author
- Barber, Glen N.
- Venue
- Nature
- Published
- 2009-09-23
- Volume
- 461
- Issue
- 7265
- Pages
- 788-792
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4664154
- OpenAlex
- W1968178474
- Semantic Scholar
- 1098beb4c76eacfcc093a88d02d02a681585e7c4
- Cited by
- 2,759
- References
- 31
- Citations by year
- 2026: 184 · 2025: 229 · 2024: 240 · 2023: 240 · 2022: 237 · 2021: 249 · 2020: 212 · 2019: 182 · 2018: 147 · 2017: 170 · 2016: 110 · 2015: 118 · 2014: 114 · 2013: 115 · 2012: 78
- FWCI
- 30.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI079336, R56AI079336, R01AI079336)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- STING, mita, Eris, type I interferon, innate immunity, herpes simplex virus type 1, TBK1, Sec5, endosomes, DNA vaccine, plasmid DNA immunization, Listeria monocytogenes, viral susceptibility, dendritic cells
- MeSH terms
- STING Protein, Animals, Antigen-Presenting Cells, DNA, Bacterial, DNA, Viral, Endoplasmic Reticulum, Fibroblasts, Immunity, Innate, Interferon Type I, Listeria monocytogenes, Membrane Proteins, Plasmids, T-Lymphocytes, Cytotoxic, Protein Serine-Threonine Kinases, Herpesvirus 1, Human, Mice, Knockout, Vaccines, DNA, Protein Transport, Cytoplasmic Vesicles, Vesicular Transport Proteins, Intracellular Space, Mice
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